Germline and somatic mutations affecting various cell proliferation pathways can affect the development of cancer in patients. For example, the acquisition of somatic mutations that confer growth advantage on the cells possessing such mutations is considered an important factor in the emergence and progression of cancerous tumors. As a number of such mutations were identified, the therapies were developed that target the proteins encoded by the mutated genes, as well as the therapies targeting the signaling pathways in which these mutated genes are involved. As these targeted therapies were implemented into clinical practice, it was discovered that mutations conferring the resistance to the targeted therapies develop and accumulate in the patients' cancerous tumors, over time rendering the therapy ineffective and making it necessary to change the course of treatment.
One example of a solid tumor cancer in which somatic tumor mutations are known to play an important role is lung cancer, which is a leading cause of cancer-related mortality in many countries, including the United States. Approximately 75% of lung cancer cases belong to non-small cell lung cancer (NSCLC), which has an overall 5-year survival rate of approximately 12%. Standard surgical treatment, as well as chemotherapy and radiotherapies are available in the field of NSCLC. However, the majority of the NSCLC cases are initially diagnosed at the inoperable late stage, and relapse is common following surgery, chemotherapy, radiotherapy and other treatments. Accordingly, treatment and diagnosis of NSCLC is a challenging medical problem. One attempt at addressing the problem was the development of the targeted drug therapies that interfere with the signaling of epidermal growth factor receptor (EGFR). EGFR, which is a member of the growth factor receptor family of tyrosine kinases, is involved in signaling pathways related to cell division and is implicated in NSCLC development and progression.
Small molecule drugs erlotinib and gefitinib, which inhibit tyrosine kinase activity of EGFR, were evaluated and approved for treatment of late stage NSCLC. It was discovered, however, that these drugs were not effective in the majority of NSCLC patients, but are most effective in a subset of patients whose tumors contain somatic EGFR mutations that lead to an increase in the tyrosine kinase activity of EGFR. This type of mutations is often termed “activating.” Somatic EGFR mutations that lead to resistance to tyrosine kinase inhibitor therapy in NSCLC patients were also discovered. This type of mutations is often termed “resistance.” Resistance mutations in EGFR tend to arise in NSCLC patients during the course of tyrosine kinase inhibitor treatment. In the cases of NSCLC that cannot be effectively treated by tyrosine kinase inhibitor therapy, such as erlotinib and gefitinib, chemotherapy, or, possibly, other targeted therapies may be used to prolong survival. To improve the chances of selecting an effective treatment for NSCLC patients, it is therefore important to determine whether the patients' NSCLC tumors contain somatic EGFR mutations that confer sensitivity or resistance to tyrosine kinase inhibitor therapy.